Electron-transfer processes have been implicated to be involved in DNA damage and repair. Yet, little is known about the mechanism(s) by which electrons migrate through nucleic acids. The following fundamental questions are addressed : (a) What is the role played by the stacked base-pairs in controlling the electronic properties of DNA? (b) How does the global structure of DNA influence the electronic coupling between a donor and an acceptor? (c) How do mutations and exogenous ligands influence the electronic properties of DNA? The specific aims of the research program are: (a) To develop a general method for the sequence-specific incorporation of metal complexes into DNA using automated DNA synthesizers; (b) To examine the structural and functional consequences of the modifications of nucleic acids with metal complexes; (c) To study the effect of the following parameters on energy- and electron-transfer processes in DNA: (i) distance between donor and acceptor (ii) conjugation between the heterocyclic bases and donors and acceptors, (iii) sequences, (iv) global conformation (v) presence of mismatches and abasic site, and (vi) presence of intercalating and non-intercalating antitumor agents. A general and modular approach for the sequence-specific incorporation of metal centers into DNA using solid-phase automated DNA synthesis is proposed. The method relies on the synthesis of metal-containing nucleosides and phosphoramidites. Various coordination complexes with a range of redox and photophysical characteristics can be incorporated into oligonucleotides of any sequence, length and modification position. The systematic investigation of the biophysical, photophysical and energy- and electron-transfer properties of the modified DNAs proposed will allow critical evaluation of the electronic properties of DNA. Understanding the ability of DNA to mediate energy- and electron- transfer over a long range will clarify the potential involvement of such processes in mutagenesis and carcinogenesis. Evaluating the mechanisms leading to the generation and migration of oxidative damage in duplex DNA will facilitate the development of novel approaches to anti-cancer therapy.
